Recently published in the International Journal of Cancer, a Chilean study has compared traditional and newer molecular screening methods for cervical cancer with findings that may have a profound impact on clinical practice and health policy in Latin America. Lead author of the study, Doctor Catterina Ferreccio spoke to chileno about cervical cancer screening in the country with particular emphasis on the national programme. Doctor Ferreccio is at the Department of Public Health, School of Medicine, Pontificia Universidad Católica de Chile.

Why is the study important?

English: In Chile, cervical cancer causes the death of more than 600 women each year and is the second leading cause of death by cancer in women of fertile age. The mortality rate for this cancer (7.6/100,000 women) is four times higher than that in developed countries. In addition, the distribution of mortality presents a large socioeconomic inequality, principally affecting women with lower socioeconomic status, whose mortality rate is one of the highest in the world. Moreover, Chilean women have changed their sexual behaviour in recent years, increasing their risk factors for cervical cancer, such as earlier initiation of sexual activity and having more sexual partners. Furthermore, the incidence of infection by high-risk Human papillomaviruses (HPV), causal agent of cervical cancer, has been increasing in Chilean women. These facts could lead to an increase in this type of cancer in Chile. It is estimated that the incidence of cervical cancer in Latin America will increase more than 75% in the next 20 years, due to demographic changes. All of this highlights the importance of improving the effectiveness and equity of the national cervical cancer prevention programme. The Chilean programme uses Papanicolaou (Pap) every three years for screening women between 25 and 64 years old, but the diagnostic accuracy of this test has never been evaluated in the country. A screening strategy that has been thoroughly studied throughout the world uses a test that detects the presence of HPV, and has demonstrated a greater sensitivity than Pap and is currently being routinely used in some developed countries. This is the first study in Chile that has evaluated the sensitivity and specificity of Pap and HPV in the clinical practice of public health centres. The study demonstrated a very low sensitivity for Pap (22%) and a sensitivity four times better for HPV (93%), the latter detecting three times more high grade lesions.

What is the technical difference between HPV and Pap; how do they work and how do they predict the presence of cancers? Why is HPV thought to be a more sensitive test?

English: The main difference is that Pap is analysed using a visual technique that results in a subjective qualitative judgement, while HPV is analysed via an automated method in which a machine produces an objective quantitative result.

The Pap smear, or conventional cervical cytology, consists of an inspection of cervical cells in order to identify cellular alterations that occur in precancerous lesions and cancer. For this test a sample of cervical cells is taken and transferred to a glass slide and sent to the laboratory for examination by a cytotechnologist or pathologist. The performance of Pap largely depends on the training and experience of both the person taking the sample and the person doing the analysis. Error can occur in different ways: at the time of sampling the spatula may not pass through the precise area of the lesion and miss the altered cells and, when inspecting the slide, it is possible that the altered cells are hidden under mucus or blood or the cytotechnologist does not exhaustively scan the slide and, therefore, may not observe them. Finally, a subjective judgment is given that depends on the criteria of the individual, who needs to assess whether what is being observed is normal or abnormal according to the shape and size of the cells’ nuclei and determine the magnitude of the lesion based on the quantity and distribution of the abnormal cells that are being observed. For these reasons the sensitivity of Pap testing varies greatly even in developing countries, with figures reported between 20% in Germany and 77% in England.

The HPV test consists of the detection in the cervix of DNA from the high-risk human papillomavirus group, the causal agent of cervical cancer, identifying, therefore, women that might be at risk of developing cancer (but do not necessarily have lesions). For this test, a sample of cells is taken from the cervix that is later put into a tube with transport medium and sent to the laboratory for analysis in special equipment. To be able to detect the DNA from HPV, only a single virus needs to be found in the sample, since the technique amplifies the signal of the genetic material, thus not requiring a sample of such high quality as the Pap. Furthermore, the sample is read by machines that give a quantitative result with a predetermined cut-off point, which makes this technique highly reproducible. Because this analysis is automated, it reduces the subjectivity and the possibility of human error and, therefore, variation in the test performance. For this reason, while lower levels of sensitivity have been reported in developing countries, the sensitivity reported in developed countries is consistently high, around 97-99%.

What are the contributing factors to the high cervical cancer rates in Chile/Latin America?

English: Women have a higher prevalence of risk factors for cervical cancer in Latin America, such as a greater number of children, early age of sexual initiation and high rate of male infidelity, contributing to an increased incidence; however, the main contributing factor to the high mortality rate in this region is the difficulty in implementing effective prevention programmes, mainly for economic reasons. The difficulties range from reaching appropriate coverage – a study in Chile demonstrated that 48% of women with cancer hadn’t undergone Pap screening in at least 10 years – to achieving good follow-up of screen-positive women, with timely diagnosis and treatment – a study in Peru showed that only 25% of women with an abnormal Pap received adequate follow-up.

Has the National cervical cancer prevention program been thoroughly evaluated over the years? How effective do you think it is? Is the decline in cervical cancer rate over time due to the program or other factors?

English: The national cervical cancer prevention programme, based on Pap screening, was introduced as a pilot study in Santiago in 1987 and was later implemented as a national programme in 1994. The mortality for this cancer decreased during this period (rates per 100 000 women of 11.8 in 1990 and 7.6 in 2009); however, this coincided with great socioeconomic development in the Chilean population and it has been demonstrated that in Latin America, income per capita is a better predictor of mortality from cervical cancer than Pap coverage. Moreover, the Chilean women’s access to higher education has tripled in the period and the proportion of women in the workforce has doubled, leading to a decrease in the fertility rate (less schooling and higher parity are considered risk factors for this cancer). Another factor that may have contributed to this decline in mortality is increased access to quality health care, including the implementation of a health reform (the AUGE plan), which means less waiting time and better follow-up care for women suspected of having cervical cancer.

Over the years, the national programme has been evaluated in terms of coverage, which increased steadily since its implementation, but has remained relatively stable in recent years (<70%), without reaching the goal of the Ministry of Health (80%). The instrument of the screening programme, the Pap test, had only been studied in terms of consistency between readings obtained at medical centre laboratories and at a reference laboratory, that is to say, if the interpretation is the same when assessing the same sample, but it had never been compared with a standard, such us colposcopy, to evaluate its sensitivity and specificity; this is the first study in Chile to do so.

The cervical cancer mortality rate by socioeconomic status is intriguing. Are the better rates in the middle classes due to education, or is this a marker for better medical treatment? What are the specific mechanisms? For example, is the environment more healthy for those better off (e.g. less pollution, better food, less stress etc?)

English: If you look at figure 3 in the article, you can see that in Chile the cervical cancer mortality rate follows a markedly unequal distribution between women with different levels of education. While women with less than eight years of education have one of the highest mortality rates in the world, women with more than 12 years of education have a mortality rate similar to developed countries (12.6 vs 1.2/100,000). Level of education is a marker of socioeconomic status. A contributing factor to the large inequality is that women from the higher levels make use of the private sector (30% of the population). The majority of private doctors carry out annual gynaecological checkups including Pap testing, which is different to practice in the public sector, where the cancer programme recommends a Pap test every three years. As shown in this study, the sensitivity of Pap is very low, but it is possible, given the slow progression of this cancer, that the Pap test repeated annually detects lesions that would have gone undetected in earlier tests, allowing women to receive treatment while the disease is still curable. On the other hand, women of low socioeconomic status have more risk factors (more children, early age of initial sexual intercourse) and a lower screening coverage (30% of female beneficiaries of the public health care system are not up to date with their Pap test).

English: This temporal correlation between the reduction in cervical cancer mortality and the implementation and increased coverage of the national programme has been interpreted, perhaps prematurely, as a success completely attributable to Pap. This test undoubtedly played a role, but as explained earlier, other factors may have had a significant influence (socioeconomic development). On the other hand, the programme has been considered more successful than it actually is, because what has been observed is the decrease in the mortality rate of the whole population; however a main contributor to the national mortality curve are women of high socioeconomic status who have a very low mortality rate, but they are seen in the private health sector, receiving annual Pap tests. In contrast, women with lower socioeconomic status, who attend the public health system and, therefore, are the beneficiaries of the national programme, still have very high mortality rates. Finally, we believe there has been some resistance from programme managers to review its impact; we hope that, in light of this study, they will take the decision to review in depth the effectiveness and cost-effectiveness of the national cervical cancer prevention programme.

Even though HPV outperformed Pap in this study, could another detection method improve on HPV in terms of sensitivity and specificity?

English: Other methods based on HPV do exist that could be more accurate, mainly by improving specificity. These methods, currently being studied internationally, include the detection of HPV RNA and oncoproteins.

What further research needs to be carried out to further improve cervical cancer detection in Chile?

English: The HPV test is being considered worldwide to replace the Pap smear in cervical cancer screening. Given the good results observed in our study using this test in three primary care centres in Santiago, it’s a very attractive alternative to be considered in Chile as well; however, given that HPV infections are very common and the majority disappear in a few years (only those that persist can lead to cancer), it is not possible to refer all the women who screen positive for HPV to a consultant for further diagnostic procedures, since it would create an unnecessary burden to the women and the health system. It is necessary, therefore, to implement a follow-up strategy for women who are HPV positive, with the aim of identifying the subgroup of women that do need to be referred for having a higher risk of lesions. Alternatives to this strategy could include visual inspection of the cervix, high quality cytology and various molecular techniques, among others. At present, we are participating in a study to determine which test is best to follow up HPV positive women.

English: The treatment of cervical cancer has not been an area of our research, but there is a point that is important to note: The progression of this cancer is relatively slow; therefore, if the lesion is diagnosed early, treatment (excision, conization or hysterectomy) is curative in most cases. Hence the importance of an effective screening process, that could avoid a large number of deaths from this cancer.